At the end of 1960's, Eli Lilly disclosed the inhibiting effect of mycophenolate sodium salt (MPS) on the growth of malignant tumor cells in warm-blooded mammals. Nowadays Novartis has introduced an enteric-coated formulation of mycophenolate sodium, referred to as Myfortic®. Mycophenolic acid can be formed either as mono- or disodium salt. South African patent No. 6804959 describes the preparation of mono- and disodium mycophenolate. Monosodium mycophenolate can be isolated after reaction of one molar equivalent of sodium methoxide with mycophenolic acid in a mixture of methanol and chloroform by precipitation with n-pentane. Preparation of the corresponding disodium salt is also described. In this case two molar equivalents of sodium methoxide were added to a solution of mycophenolic acid in 2:1 benzene-chloroform mixture. The evaporated material was crystallized from aqueous acetone.
The synthetic route of WO 97/38689 is identical to the one described in South African patent No. 6804959. The compound may be obtained in crystalline form by recrystallization from acetone/ethanol if necessary with water (m.p. 189-191° C.).
The present invention relates to the solid state physical properties of mycophenolate sodium. These properties may be influenced by controlling the conditions under which mycophenolate sodium is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic Form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state C NMR spectrometry and infrared spectrometry.
WO2004/020426 discloses preparation of sodium mycophenolate by reacting mycophenolic acid or its ammonium or dibenzyl-amine salt with a sodium salt of C2 to C10 carboxylic acid. Mycophenolic acid is converted to its ammonium salt by reacting with ammonia. This compound is reacted with sodium acetate to obtain the sodium salt of mycophenolic acid.
WO 2004/064806 discloses additional polymorphic forms of mycophenolate sodium and acid.
Monosodium Salt
South African patent No. 68/4,959 provides an example for preparing monosodium mycophenolate salt (Example 3). Sodium methylate in anhydrous methanol was added to mycophenolic acid in chloroform, then the monosodium salt was precipitated by adding n-pentane and collected by filtration and vacuum dried.
Acta Chrtystallographica Sect. C, (2000), C56, 432-433 describes another process for producing monosodium mycophenolate. A methanolic solution of the commercially available mycophenolic acid was treated with one equivalent of sodium methanolate. After stirring for 1 hour at room temperature, the solvent was evaporated to dryness in vacuum. The melting point of the product was 463 K (190° C.). Single crystals were grown by evaporation and cooling of a water/ethyl acetate solution from about 323K to room temperature. The crystal structure of the produced sodium mycophenolate measured by single crystal diffractometer is also described.
Based on the given crystal parameters, the calculated powder diffractogram done by the inventors of the present invention show that the crystal form obtained is the crystal form denominated Form M2. Form M2 is an anhydrous form. Form M2 is characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2 theta (FIG. 3) and FTIR peaks at 1719, 1571, 1317, 1266, 1134 and 927 cm-1 (FIG. 4). Form M2 may be further characterized by XRD peaks at 13.6 and 19.0±0.2 degrees 2 theta. Form M2 may be further characterized by IR peaks at 1194, 1108, 1075, 1034, 971, 875, 826, 794 and 722 cm-1. Form M2 may be further characterized by a DSC curve (FIG. 43).
PCT 97/38689 describes sodium mycophenolate salts as known from South African Patent. It also describes the process for obtaining monosodium salt in crystalline form by recrystallization from acetone/ethanol if necessary with water. The melting point provided is 189-191° C.
J. Med. Chem. (1996), 39, 1236-1242 describes treating a solution of mycophenolic acid in ethanol with equimolar sodium ethylate at room temperature and stirring for 30 minutes. The solvent was evaporated in vacuum.
J. Pharm. Sciences (1970), 59(8), 1157-1159 asserts that monosodium mycophenolate may be formed by adjusting the slurry of mycophenolic acid to pH 7-8 with sodium hydroxide. No physical data is provided.
Disodium Salt
South African patent No. 68/4,959 provides an example for producing disodium mycophenolate (Example 2). Mycophenolic acid was dissolved in benzene:chloroform 2:1 solvent mixture and sodium methoxide dissolved in anhydrous methanol was added to it. The solution was stirred for 15-20 minutes, evaporated to dryness and redissolved in water. Crystallization was effected by the addition of acetone to the hot water solution and chilling overnight. No physical data was given.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.